Dr. Richardson noted that relapsed, refractory disease remains the greatest clinical challenge in myeloma. This category is defined as disease progression on salvage therapy or within 60 days. The patient population with relapsed, refractory myeloma is older, has increased beta-2-microglobulin, lower serum albumin, lower platelet counts, cytogenetic abnormalities, renal dysfunction, extensive bone disease, and, as treatment for myeloma improves, increased likelihood of extramedullary disease. All of these factors are associated with higher risk disease. However, at least some of these high risk factors may be overcome with treatment using newer agents; nevertheless, the challenges presented in relapsed, refractory disease provide a rationale for combination therapies. The list of novel combinations is increasing, and includes melphalan plus prednisone combined with thalidomide with and without bortezomib or with lenalidomide; the recently approved combination of Doxil (pegylated liposomal doxorubicin) with bortezomib; and a combination Dr. Richardson characterizes as one of his favorites, lenalidomide plus bortezomib. This regimen is steroid-sparing, and appears to target both the bone marrow microenvironment and extramedullary disease, with an acceptable safety profile. Balancing efficacy and toxicity in the challenging setting of drug resistance requires a tailored approach, Dr. Richardson observed. In addition, new agents are entering clinical trials, e.g., the Akt inhibitor, perifosine, histone deacetylase (HDAC) inhibitors, tanespimycin (KOS-953), a heat shock protein (Hsp) 90 inhibitor. As a result, long term patient survival, increasing treatment options, and good patient quality of life continue to be seen.